4i1p

From Proteopedia

Human MALT1 (caspase-IG3) in complex with activity based-probe

PDB ID 4i1p

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Structural highlights

4i1p is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.403Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MALT1_HUMAN Note=A chromosomal aberration involving MALT1 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(11;18)(q21;q21) with BIRC2. This translocation is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphoma.

Function

MALT1_HUMAN Enhances BCL10-induced activation of NF-kappa-B. Involved in nuclear export of BCL10. Binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity. Has ubiquitin ligase activity. MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion.^[1] ^[2] ^[3]

Publication Abstract from PubMed

MALT1 paracaspase is activated upon antigen receptor stimulation to promote lymphocyte activation. In addition, deregulated MALT1 protease activity drives survival of distinct lymphomas such as the activated B cell type of diffuse large B cell lymphoma (ABC-DLBCL). Here, we designed fluorophore or biotin-coupled activity based-probes (ABP) that covalently modify the active center of MALT1. MALT1-ABPs are exclusively labeling an active modified full length form of MALT1 upon T cell stimulation. Further, despite the CARMA1 requirement for initial MALT1 activation, the MALT1-ABPs show that protease activity is not confined to the high-molecular CARMA1-BCL10-MALT1 (CBM) complex. Using biotin-coupled ABPs, we developed a robust assay for sensitive and selective detection of active MALT1 in cell lines, primary lymphocytes, and DLBCL tumor biopsies. Taken together, MALT1-ABPs represent powerful chemical tools to measure cellular MALT1 activation, determine efficacy of small molecule inhibitors, and classify lymphomas based on MALT1 activity status.

Activity-Based Probes for Detection of Active MALT1 Paracaspase in Immune Cells and Lymphomas.,Eitelhuber AC, Vosyka O, Nagel D, Bognar M, Lenze D, Lammens K, Schlauderer F, Hlahla D, Hopfner KP, Lenz G, Hummel M, Verhelst SH, Krappmann D Chem Biol. 2014 Dec 30. pii: S1074-5521(14)00420-7. doi:, 10.1016/j.chembiol.2014.10.021. PMID:25556945^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lucas PC, Yonezumi M, Inohara N, McAllister-Lucas LM, Abazeed ME, Chen FF, Yamaoka S, Seto M, Nunez G. Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J Biol Chem. 2001 Jun 1;276(22):19012-9. Epub 2001 Mar 21. PMID:11262391 doi:10.1074/jbc.M009984200
↑ Zhou H, Wertz I, O'Rourke K, Ultsch M, Seshagiri S, Eby M, Xiao W, Dixit VM. Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature. 2004 Jan 8;427(6970):167-71. Epub 2003 Dec 24. PMID:14695475 doi:10.1038/nature02273
↑ Rebeaud F, Hailfinger S, Posevitz-Fejfar A, Tapernoux M, Moser R, Rueda D, Gaide O, Guzzardi M, Iancu EM, Rufer N, Fasel N, Thome M. The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol. 2008 Mar;9(3):272-81. doi: 10.1038/ni1568. Epub 2008 Feb 10. PMID:18264101 doi:10.1038/ni1568
↑ Eitelhuber AC, Vosyka O, Nagel D, Bognar M, Lenze D, Lammens K, Schlauderer F, Hlahla D, Hopfner KP, Lenz G, Hummel M, Verhelst SH, Krappmann D. Activity-Based Probes for Detection of Active MALT1 Paracaspase in Immune Cells and Lymphomas. Chem Biol. 2014 Dec 30. pii: S1074-5521(14)00420-7. doi:, 10.1016/j.chembiol.2014.10.021. PMID:25556945 doi:http://dx.doi.org/10.1016/j.chembiol.2014.10.021